PROJECT ABSTRACT SUMMARY Over one million Americans suffer a heart attack (myocardial infarction) each year while 250,000 Americans die each year from congestive heart failure. The societal and financial impacts are tremendous, with cardiovascular diseases accounting for 8% of annual U.S. health care costs in 2007. In adult tissues such as heart, the capacity for self-regeneration is limited. Stem cells hold out the potential of almost unimaginable medical breakthroughs for the treatment of diseases. To harness the plasticity of hPSCs and realize their utility in regenerative medicine, we need to develop new culture approaches that more closely mimic the native environment, and possess the ability to either promote differentiation to specific lineages or propagate stem cells without the loss of stem cells. In this project, we introduce a new generation of platforms, based on the use of carbon nanotubes (CNTs), that allows for control over the temporal and nano-scale spatial organization of microenvironmental signals. The cornerstone concept motivating this effort is the unique ability of CNTs to dynamically couple electrical and mechanical properties. Our long term vision is to use these platforms to program pluripotent stem cells for cardiac repair. The governing hypothesis of this study is that the addition of electromechanical stimulation that mimics the time-scale of the in-vivo environment enhances the cardiogenic differentiation of stem cells and improves the survival, proliferation and contractibility of differentiated cardiomyocytes. To test our hypothesis, our study will entail two specific aims: (1) develop CNT-collagen substrates with dynamically controllable electromechanical properties, and (2) determine hiPSC cardiogenic differentiation response to electromechanical stimulation. The insight gained from this study will enable the manipulation of in-vitro cell culture conditions for cardiac repair. Overall, the scientific understanding of the relationships between environmental signals and stem cell differentiation will potentially provide a basis for designing appropriate culture systems that will facilitate stem cell use in clinical settings and regenerative therapies.